The objectives of this proposal are to elucidate the mechanisms by which insulin decreases the renal excretion of phosphate and sodium in normal kidney and in kidneys of animals with experimentally induced diabetes mellitus. Specifically, we propose to determine if insulin increases renal tubular reabsorption of phosphate and sodium alone or via its antagonism to other hormones (PTH, glucagon) which increase the phosphate and sodium excretion. We will investigate if insulin exerts its renal effects through mediation of cyclic AMP (cAMP) or cyclic GMP (cGMP) systems. We will determine the direct and/or indirect effects of insulin on 1) renal cortical levels and urinary excretion of nephrogenous cAMP and cGMP and 2) on the immunocytochemical localization of these nucleotides in renal cortical cells. We will also examine the effect of insulin on elements of renal cortical protein phosphorylation: 1) the activation of cAMP and cGMP protein kinases, 2) on heat stable protein kinase modulators and 3) on cyclic nucleotide independent phosphoprotein metabolism. In these experiments we will also analyze if the effects of insulin on the cellular dynamics of cAMP and cGMP are dependent on calcium and if insulin acts on enzymes of cyclic nucleotide metabolism and on transcellular fluxes of cyclic nucleotides. We will explore if insulin action on the kidney can be mimicked by cyclic nucleotide analogs. Studies on animals with experimentally-induced diabetes mellitus will reveal if diabetic kidneys have an altered responsiveness to insulin in terms of its effects on phosphate and sodium transport and what the underlying causes of this altered sensitivity are. These studies have fundamental implications for the understanding of the mechanisms by which insulin directly or indirectly influences the renal excretion of phosphate and sodium and its role in the pathogenesis of diabetes mellitus and associated complications.